| Background and aimHypertension is one of the most common cardiovascular diseases with artery and ventricular remodeling as its main pathologic changes. Recently, researchers realize that myocardiocyte apoptosis is a major factor for decreasing amount of myocardia in ventricular remodeling, in which process there are many humoral factors take part Renin-angiotensin system (RAS) is overly activated when hypertension occurs, and the angiotensin II (Ang II) with high level in the circulation and in the myocardium especially plays an important role in apoptosis. Ang II combines its receptor-angiotensin 1 receptor (AT1).This can induce myocardiocyte apoptosis through many kinds of pathways. Tumor necrosis factor-α(TNF-α) also plays an important role in the process of myocardiocyte apoptosis in hypertension. It combines TNF-αreceptor I, then induces apoptosis through death receptor (DR) signal pathway. Many studies have shown that endothelial nitric oxide synthase (eNOS) down-regulated and endothelin-1 (ET-1) up-regulated in ( spontaneously hypertensive rats(SHR) can induce myocardiocyte apoptosis. Theoretically, to interfere with myocardiocyte apoptosis induced by humoral factors, may prevent or retard the process of ventricular remodeling during hypertension.Statinlike drugs contain many other pharmacologic effects except for regulating blood lipid, such as reducing scleratheromatous plaque, anti-aggregation of platelets, anti-inflammation, improving function of endothelia and hemorheology. Recently, it has been reported that statins upregulate eNOS expression and activity, downregulate ET-1 , Ang II expression, and inhibit the activity of TNF-α. We hypothesized that statins maybe have interfered with ventricular remodeling partially related to its humoral factor modulation and antagonism, and preventing myocardiocyte apoptosis for hypertension. Therefore, we aim at studying the mechanisms of atorvastatin to retard myocardiocyte apoptosis and improve left ventricular function through detecting the expression of TNF-α, Ang II, ET-1, eNOS activity, myocardiocyte apoptosis index and left ventricular remodeling indexes in SHR, and supply new experiment proofs and theory base for statinlike drugs to retard ventricular remodeling in hypertension.Methods1. Twenty healthy male spontaneously hypertensive rats weighted 184.7±16.2 gram were randomly divided into atovastatin treatment group(ATV group, n=10) and 0.9% NaCl diet control group(NS group, n=10). At the same time, ten Wistar-Kyoto rats (WKY), with same weights and week age (16 weeks) to spontaneously hypertensive rats, were used as normal control group (WKY group). Rats in ATV group were treated with atorvastatin (gastric gavage, 40mg/kg/d in 2 ml of 0.9% NaCl) for 10 weeks, and rats in NS group and WKY group were treated only with 0.9% NaCl of the same volume in same time.2. Treatment ten weeks later, two-dimensional echocardiography was performed with a phased-array echocardiographic machine through; subcostal views including left ventricular end-diastolic diameter (LVEDd), left ventricular ejection fraction (LVEF) and fractional shortening (FS) were obtained. Hemodynamics data such as left ventricular end diastolic pressure (LVEDP), LV systolic pressure (LVSP), systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were gathered. We measured the body weight, heart weight, left ventricular weight, heart weight (heart weight/body weight) and left ventricular weight index (left ventricular weight/body weight) of rats with electronic balance. In addition, myocardiocyte apoptosis index were examined by TUNEL, Ang II, ET-1 and TNF-αprotein concentration in the serum was analyzed by radioimmunoassay, The activity of eNOS in myocardia was get by photocolorimetric method.Results1. Compared with ATV group and WKY group, LVEDP of NS group significantly increased (P<0.05), while SBP, DBP and LVSP significantly decreased (P<0.05), but HR did not change (P>0.05). Compared with NS group, LVEDP in the ATV group significantly decreased (P<0.05) while SBP, DBP and LVSP significantly increased (P<0.05).2.After treatment for ten weeks, there were no significant differences in body weight among the three groups (P>0.05). The heart weight, the heart weight index and left ventricular weight index were significantly higher in the NS group and ATV group (P <0.05), but those in ATV group markedly reduced (P<0.05) compared with the NS group.3. Compared with the WKY group, there were significant increased LVEDd (P<0.05), decreased LVEF and FS (P<0.05) in the NS group and ATV group. But compared with the NS group, LVEDd significantly decreased in ATV group (P<0.05), while LVEF and FS markedly increased (P<0.05).4. In the NS group and ATV group, the left ventricular myocardiocyte apoptosis index, the TNF-α, AngII, and ET-1 concentration in the serum and expression in the left ventricular myocardia were significantly higher than these in the WKY group (P< 0.05), The activity of eNOS in the left ventricular myocardia obviously decreased (P < 0.05). But compared with the NS group, ATV group displayed significant reductions of these indexes except eNOS (P<0.05). But the activity of eNOS in the left ventricular myocardia significant increased (P<0.05).Conclusions1. During the ventricular remodeling, the expression of TNF-α, AngII and ET-1 as well as the myocardium apoptosis index in the myocardium increase in SHR. But the indexes of hemodynamics, ventricular function and the activity of eNOS in myocardia decrease.2. Atorvastatin could inhibit the expression of TNF-α, AngII and ET-1 in myocardia or the level of those in the serum, increase the activity of eNOS in myocardia, reduce the myocardiocyte apoptosis index, retard ventricular remodeling, improve hemodynamics and cardiac function.3. Atorvastatin inhibits myocardium apoptosis, retards cardiac remodeling and improves left ventricular function of SHR, which may be related to these effects that it can decrease the expression of TNF-α, AngII and ET-1, and increase the activity of eNOS.
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